30 results on '"Schneider, Stefan W."'
Search Results
2. C-reactive protein flare predicts response to checkpoint inhibitor treatment in melanoma.
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Kött J, Zimmermann N, Zell T, Heidrich I, Geidel G, Rünger A, Smit DJ, Merkle M, Parnian N, Hansen I, Hoehne I, Abeck F, Torster L, Weichenthal M, Pantel K, Schneider SW, and Gebhardt C
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- Humans, Male, Female, Middle Aged, Aged, Adult, Prospective Studies, Biomarkers, Tumor blood, Aged, 80 and over, Melanoma drug therapy, Melanoma blood, C-Reactive Protein metabolism, C-Reactive Protein analysis, Immune Checkpoint Inhibitors therapeutic use, Skin Neoplasms drug therapy, Skin Neoplasms pathology, Skin Neoplasms blood
- Abstract
Background: The treatment of melanoma has been revolutionized by the use of immune checkpoint inhibition (ICI), but many patients do not benefit. Furthermore, immune-related adverse events may occur during therapy. A predictive biomarker is needed to reliably identify patients benefitting. In lung, renal cell and bladder cancer early C-reactive protein (CRP) kinetics were shown to be a predictive biomarker for ICI., Objective: Here, we investigate early CRP kinetics as predictive biomarker for ICI in melanoma patients., Methods: Two independent prospectively collected cohorts were analysed: Cohort 1 (n = 87) with advanced and Cohort 2 (n = 99) with completely resected melanoma. Patients were stratified by in the dynamics of CRP after ICI initiation: A doubling of baseline CRP within 30 days followed by at least a 30% drop within 3 months was classified as a CRP flare. If no doubling of CRP was reported, but a 30% drop within 3 months, patients were classified as CRP responders and all others as CRP non-responders. Analysed factors included clinical characteristics like S100B and LDH. Median follow-up was 1.5 and 1.7 years for Cohorts 1 and 2., Results: In Cohort 1 CRP flare (n = 12), CRP responders (n = 43) and CRP non-responders (n = 32) with a progression-free survival (PFS) of 0.7, 0.6 and 0.2 years (p = 0.017) and an overall survival (OS) of 2.2, 1.5 and 1.0 years (p = 0.014), respectively. Multivariable Cox analysis showed an independent risk reduction of progression for CRP responders by 62% compared to CRP non-responders (p = 0.001). In Cohort 2 CRP flare (n = 13), CRP responders (n = 70) and CRP non-responders (n = 16) the log-rank analysis showed a significant difference between OS and recurrence-free survival (RFS) curves (p = 0.046 and p = 0.049)., Conclusion: Early CRP kinetics could indicate a response to ICI with improved OS and RFS/PFS. CRP flare and CRP response indicating significantly improved outcomes compared to CRP non-responders., (© 2024 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology.)
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- 2024
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3. Mutation analysis in individual circulating tumor cells depicts intratumor heterogeneity in melanoma.
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Sementsov M, Ott L, Kött J, Sartori A, Lusque A, Degenhardt S, Segier B, Heidrich I, Volkmer B, Greinert R, Mohr P, Simon R, Stadler JC, Irwin D, Koch C, Andreas A, Deitert B, Thewes V, Trumpp A, Schneeweiss A, Belloum Y, Peine S, Wikman H, Riethdorf S, Schneider SW, Gebhardt C, Pantel K, and Keller L
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- Humans, DNA Mutational Analysis, Cell Line, Tumor, Genetic Heterogeneity, Mass Spectrometry, Female, Male, Melanoma genetics, Melanoma pathology, Neoplastic Cells, Circulating pathology, Neoplastic Cells, Circulating metabolism, Circulating Tumor DNA genetics, Circulating Tumor DNA blood, Mutation
- Abstract
Circulating tumor DNA (ctDNA) is the cornerstone of liquid biopsy diagnostics, revealing clinically relevant genomic aberrations from blood of cancer patients. Genomic analysis of single circulating tumor cells (CTCs) could provide additional insights into intra-patient heterogeneity, but it requires whole-genome amplification (WGA) of DNA, which might introduce bias. Here, we describe a novel approach based on mass spectrometry for mutation detection from individual CTCs not requiring WGA and complex bioinformatics pipelines. After establishment of our protocol on tumor cell line-derived single cells, it was validated on CTCs of 33 metastatic melanoma patients and the mutations were compared to those obtained from tumor tissue and ctDNA. Although concordance with tumor tissue was superior for ctDNA over CTC analysis, a larger number of mutations were found within CTCs compared to ctDNA (p = 0.039), including mutations in melanoma driver genes, or those associated with resistance to therapy or metastasis. Thus, our results demonstrate proof-of-principle data that CTC analysis can provide clinically relevant genomic information that is not redundant to tumor tissue or ctDNA analysis., (© 2024. The Author(s).)
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- 2024
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4. Prognostic value of von Willebrand factor levels in patients with metastatic melanoma treated by immune checkpoint inhibitors.
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Stadler JC, Keller L, Mess C, Bauer AT, Koett J, Geidel G, Heidrich I, Vidal-Y-Sy S, Andreas A, Stramaglia C, Sementsov M, Haberstroh W, Deitert B, Hoehne IL, Reschke R, Haalck T, Pantel K, Gebhardt C, and Schneider SW
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- Humans, Immune Checkpoint Inhibitors pharmacology, Immune Checkpoint Inhibitors therapeutic use, Prognosis, Prospective Studies, Melanoma drug therapy, von Willebrand Factor metabolism
- Abstract
Background: An increased incidence of thrombotic complications associated with an increased mortality rate has been observed under immune checkpoint inhibition (ICI). Recent investigations on the coagulation pathways have highlighted the direct role of key coagulatory proteins and platelets in cancer initiation, angiogenesis and progression. The aim of this study was to evaluate the prognostic value of von Willebrand factor (vWF) and its regulatory enzyme a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13), D-dimers and platelets in a cohort of patients with metastatic melanoma receiving ICI., Methods: In a prospective cohort of 83 patients with metastatic melanoma, we measured the systemic levels of vWF-antigen (vWF:Ag), ADAMTS13 activity, D-dimers and platelets, before the beginning of the treatment (baseline), and 6, 12 and 24 weeks after. In parallel, we collected standard biological parameters used in clinical routine to monitor melanoma response (lactate deshydrogenase (LDH), S100). The impact of neutrophil-to-lymphocyte ratio (NLR) and C-reactive protein (CRP) on overall survival (OS) in patients receiving ICI was assessed. Univariable and multivariable Cox proportional models were then used to investigate any potential association of these parameters to clinical progression (progression-free survival (PFS) and OS). Baseline values and variations over therapy course were compared between primary responders and resistant patients., Results: Patients with melanoma present with dysregulated levels of vWF:Ag, ADAMTS13 activity, D-dimers, LDH, S100 and CRP at the beginning of treatment. With a median clinical follow-up of 26 months, vWF:Ag interrogated as a continuous variable was significantly associated with PFS in univariate and multivariate analysis (HR=1.04; p=0.007). Lower values of vWF:Ag at baseline were observed in the primary responders group (median: 29.4 µg/mL vs 32.9 µg/mL; p=0.048) when compared with primary resistant patients. As for OS, we found an association with D-dimers and ADAMTS13 activity in univariate analysis and vWF:Ag in univariate and multivariate analysis including v-raf murine sarcoma viral oncogene homolog B1 (BRAF) mutation and Eastern Cooperative Oncology Group (ECOG) performance status. Follow-up over the course of treatment depicts different evolution profiles for vWF:Ag between the primary response and resistance groups., Conclusions: In this prospective cohort, coagulatory parameters such as ADAMTS13 activity and D-dimers are associated with OS but baseline vWF:Ag levels appeared as the only parameter associated with response and OS to ICI. This highlights a potential role of vWF as a biomarker to monitor ICI response of patients with malignant melanoma., Competing Interests: Competing interests: J-CS, LK, ATB, CM, AA, SVS, MS, WH, CS, BD, ILH, RR, TH, JK, IH, GG, KP and SWS declare no competing interest. CG is a member of the advisory board and has received honoraria and travel expenses from Almirall, Amgen, Beiersdorf, BioNTech, Bristol-Myers Squibb, Immunocore, Janssen, MSD Sharp & Dohme, Novartis, Pierre-Fabre, Roche, Sanofi Genzyme, SUN Pharma, Sysmex/Inostics, outside the submitted work. CG holds shares of Dermagnostix., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
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- 2023
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5. Neutrophils activated by membrane attack complexes increase the permeability of melanoma blood vessels.
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Liu X, Wang Y, Bauer AT, Kirschfink M, Ding P, Gebhardt C, Borsig L, Tüting T, Renné T, Häffner K, Hu W, Schneider SW, and Gorzelanny C
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- Animals, Complement System Proteins, Humans, Mice, Permeability, Complement Membrane Attack Complex immunology, Endothelium, Vascular physiopathology, Extracellular Traps, Melanoma blood supply, Melanoma immunology, Melanoma pathology, Neutrophils immunology, Tumor Microenvironment
- Abstract
The microenvironment of malignant melanomas defines the properties of tumor blood vessels and regulates infiltration and vascular dissemination of immune and cancer cells, respectively. Previous research in other cancer entities suggested the complement system as an essential part of the tumor microenvironment. Here, we confirm activation of the complement system in samples of melanoma patients and murine melanomas. We identified the tumor endothelium as the starting point of the complement cascade. Generation of complement-derived C5a promoted the recruitment of neutrophils. Upon contact with the vascular endothelium, neutrophils were further activated by complement membrane attack complexes (MACs). MAC-activated neutrophils release neutrophil extracellular traps (NETs). Close to the blood vessel wall, NETs opened the endothelial barrier as indicated by an enhanced vascular leakage. This facilitated the entrance of melanoma cells into the circulation and their systemic spread. Depletion of neutrophils or lack of MAC formation in complement component 6 (C6)-deficient animals protected the vascular endothelium and prevented vascular intravasation of melanoma cells. Our data suggest that inhibition of MAC-mediated neutrophil activation is a potent strategy to abolish hematogenous dissemination in melanoma.
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- 2022
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6. Heparan sulfate dependent binding of plasmatic von Willebrand factor to blood circulating melanoma cells attenuates metastasis.
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Wang Y, Liu X, Obser T, Bauer AT, Heyes M, Starzonek S, Zulal M, Opitz K, Ott L, Riethdorf S, Lange T, Pantel K, Bendas G, Schneider SW, Kusche-Gullberg M, and Gorzelanny C
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- Animals, Cell Adhesion, Mice, Mice, Knockout, Neoplasm Metastasis, Protein Binding, Heparitin Sulfate metabolism, Melanoma metabolism, Melanoma pathology, von Willebrand Factor genetics, von Willebrand Factor metabolism
- Abstract
Heparan sulfate (HS), a highly negatively charged glycosaminoglycan, is ubiquitously present in all tissues and also exposed on the surface of mammalian cells. A plethora of molecules such as growth factors, cytokines or coagulation factors bear HS binding sites. Accordingly, HS controls the communication of cells with their environment and therefore numerous physiological and pathophysiological processes such as cell adhesion, migration, and cancer cell metastasis. In the present work, we found that HS exposed by blood circulating melanoma cells recruited considerable amounts of plasmatic von Willebrand factor (vWF) to the cellular surface. Analyses assisted by super-resolution microscopy indicated that HS and vWF formed a tight molecular complex. Enzymatic removal of HS or genetic engineering of the HS biosynthesis showed that a reduced length of the HS chains or complete lack of HS was associated with significantly reduced vWF encapsulation. In microfluidic experiments, mimicking a tumor-activated vascular system, we found that vWF-HS complexes prevented vascular adhesion. In line with this, single molecular force spectroscopy suggested that the vWF-HS complex promoted the repulsion of circulating cancer cells from the blood vessel wall to counteract metastasis. Experiments in wild type and vWF knockout mice confirmed that the HS-vWF complex at the melanoma cell surface attenuated hematogenous metastasis, whereas melanoma cells lacking HS evade the anti-metastatic recognition by vWF. Analysis of tissue samples obtained from melanoma patients validated that metastatic melanoma cells produce less HS. Transcriptome data further suggest that attenuated expression of HS-related genes correlate with metastases and reduced patients' survival. In conclusion, we showed that HS-mediated binding of plasmatic vWF to the cellular surface can reduce the hematogenous spread of melanoma. Cancer cells with low HS levels evade vWF recognition and are thus prone to form metastases. Therefore, therapeutic expansion of the cancer cell exposed HS may prevent tumor progression., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing financial interests., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)
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- 2022
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7. Incidence of pulmonary embolism and impact on mortality in patients with malignant melanoma.
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Rennebaum S, Schneider SW, Henzler T, Desch A, Weiß C, Haubenreisser H, Goerdt S, Morelli JN, Utikal JS, Schoenberg SO, and Riffel J
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- Humans, Incidence, Retrospective Studies, Melanoma diagnostic imaging, Pulmonary Embolism diagnostic imaging, Pulmonary Embolism epidemiology, Ventricular Dysfunction, Right etiology
- Abstract
Purpose: Pulmonary embolism (PE) occurs frequently in patients with malignant melanoma (MM). The aim of this study is to determine the incidence of PE in patients with MM and to assess the clinical characteristics and mortality of MM patients with PE., Material and Methods: Medical records from 381 MM patients who underwent contrast-enhanced computed tomography were evaluated. Imaging parameters including location of PE and measurements of right heart dysfunction and clinical parameters including D-Dimer levels, local and distant tumor stage and time of death were analyzed., Results: PE was found in 23/381 (6%) MM patients, whereby 17/23 (74%) were detected incidentally and only 6/23 (26%) were symptomatic. The presence of PE significantly correlated with elevated D-Dimers (p < 0.001), right ventricular dysfunction (p = 0.04), higher local tumor stage (≥T3) (p = 0.05), presence of visceral (p = 0.02) or cerebral metastases (p = 0.03) and increased mortality (p = 0.05). Further, patients with central PE showed an increased mortality compared to peripheral PE (p = 0.03), but no correlation was found between the localization of PE and the occurrence of clinical symptoms (p = 0.36)., Conclusion: PE in patients with MM often occurs without clinical symptoms and is indicative for advanced disease and a poorer prognosis., (Copyright © 2022 Elsevier Inc. All rights reserved.)
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- 2022
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8. Adjuvant pembrolizumab-related hyperprogression in stage III melanoma.
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Ammann NL, Geidel G, Schneider SW, and Gebhardt C
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- Antibodies, Monoclonal, Humanized adverse effects, Humans, Neoplasm Staging, Melanoma drug therapy, Melanoma pathology, Skin Neoplasms drug therapy, Skin Neoplasms pathology
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- 2021
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9. Melanoma Associated Chitinase 3-Like 1 Promoted Endothelial Cell Activation and Immune Cell Recruitment.
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Ramos-Espinosa G, Wang Y, Brandner JM, Schneider SW, and Gorzelanny C
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- Animals, Blood Vessels growth & development, Blood Vessels immunology, Blood Vessels pathology, Cell Line, Tumor, Endothelial Cells immunology, Endothelial Cells pathology, Endothelium, Vascular growth & development, Endothelium, Vascular immunology, Endothelium, Vascular pathology, Extracellular Matrix drug effects, Gene Expression Regulation, Neoplastic drug effects, Glycosaminoglycans pharmacology, HEK293 Cells, Human Umbilical Vein Endothelial Cells, Humans, Melanoma immunology, Melanoma pathology, Microfluidic Analytical Techniques, Neovascularization, Pathologic immunology, Neovascularization, Pathologic pathology, Protein Binding genetics, Protein Binding immunology, Chemokine CCL2 genetics, Chitinase-3-Like Protein 1 genetics, Melanoma genetics, Neovascularization, Pathologic genetics, Vascular Endothelial Growth Factor A genetics
- Abstract
Chitinase 3-like 1 (CHI3L1) is an enzymatically inactive mammalian chitinase that is associated with tumor inflammation. Previous research indicated that CHI3L1 is able to interact with different extracellular matrix components, such as heparan sulfate. In the present work, we investigated whether the interaction of CHI3L1 with the extracellular matrix of melanoma cells can trigger an inflammatory activation of endothelial cells. The analysis of the melanoma cell secretome indicated that CHI3L1 increases the abundance of various cytokines, such as CC-chemokine ligand 2 (CCL2), and growth factors, such as vascular endothelial growth factor A (VEGF-A). Using a solid-phase binding assay, we found that heparan sulfate-bound VEGF-A and CCL2 were displaced by recombinant CHI3L1 in a dose-dependent manner. Microfluidic experiments indicated that the CHI3L1 altered melanoma cell secretome promoted immune cell recruitment to the vascular endothelium. In line with the elevated VEGF-A levels, CHI3L1 was also able to promote angiogenesis through the release of extracellular matrix-bound pro-angiogenic factors. In conclusion, we showed that CHI3L1 is able to affect the tumor cell secretome, which in turn can regulate immune cell recruitment and blood vessel formation. Accordingly, our data suggest that the molecular targeting of CHI3L1 in the course of cancer immunotherapies can tune patients' response and antitumoral inflammation.
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- 2021
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10. Local blood coagulation drives cancer cell arrest and brain metastasis in a mouse model.
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Feinauer MJ, Schneider SW, Berghoff AS, Robador JR, Tehranian C, Karreman MA, Venkataramani V, Solecki G, Grosch JK, Gunkel K, Kovalchuk B, Mayer FT, Fischer M, Breckwoldt MO, Brune M, Schwab Y, Wick W, Bauer AT, and Winkler F
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- Animals, Brain Neoplasms etiology, Brain Neoplasms pathology, Breast Neoplasms blood, Breast Neoplasms complications, Cell Cycle Checkpoints, Disease Models, Animal, Female, Humans, Melanoma blood, Melanoma complications, Mice, Thrombosis etiology, Thrombosis pathology, von Willebrand Factor analysis, Blood Coagulation, Brain Neoplasms blood, Breast Neoplasms pathology, Melanoma pathology, Neoplastic Cells, Circulating pathology, Thrombosis blood
- Abstract
Clinically relevant brain metastases (BMs) frequently form in cancer patients, with limited options for effective treatment. Circulating cancer cells must first permanently arrest in brain microvessels to colonize the brain, but the critical factors in this process are not well understood. Here, in vivo multiphoton laser-scanning microscopy of the entire brain metastatic cascade allowed unprecedented insights into how blood clot formation and von Willebrand factor (VWF) deposition determine the arrest of circulating cancer cells and subsequent brain colonization in mice. Clot formation in brain microvessels occurred frequently (>95%) and specifically at intravascularly arrested cancer cells, allowing their long-term arrest. An extensive clot embedded ∼20% of brain-arrested cancer cells, and those were more likely to successfully extravasate and form a macrometastasis. Mechanistically, the generation of tissue factor-mediated thrombin by cancer cells accounted for local activation of plasmatic coagulation in the brain. Thrombin inhibition by treatment with low molecular weight heparin or dabigatran and an anti-VWF antibody prevented clot formation, cancer cell arrest, extravasation, and the formation of brain macrometastases. In contrast, tumor cells were not able to directly activate platelets, and antiplatelet treatments did reduce platelet dispositions at intravascular cancer cells but did not reduce overall formation of BMs. In conclusion, our data show that plasmatic coagulation is activated early by intravascular tumor cells in the brain with subsequent clot formation, which led us to discover a novel and specific mechanism that is crucial for brain colonization. Direct or indirect thrombin and VWF inhibitors emerge as promising drug candidates for trials on prevention of BMs., (© 2021 by The American Society of Hematology.)
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- 2021
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11. Pre-analytical factors affecting the establishment of a single tube assay for multiparameter liquid biopsy detection in melanoma patients.
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Schneegans S, Lück L, Besler K, Bluhm L, Stadler JC, Staub J, Greinert R, Volkmer B, Kubista M, Gebhardt C, Sartori A, Irwin D, Serkkola E, Af Hällström T, Lianidou E, Sprenger-Haussels M, Hussong M, Mohr P, Schneider SW, Shaffer J, Pantel K, and Wikman H
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- Aged, Biomarkers, Tumor blood, Biomarkers, Tumor genetics, Cell Line, Tumor, Extracellular Vesicles genetics, Extracellular Vesicles metabolism, Extracellular Vesicles ultrastructure, Female, High-Throughput Nucleotide Sequencing, Humans, Male, Melanoma pathology, MicroRNAs genetics, Microscopy, Electron, Transmission, Mutation, Neoplasm Staging, Neoplastic Cells, Circulating metabolism, Circulating Tumor DNA blood, Liquid Biopsy instrumentation, Liquid Biopsy methods, Melanoma blood, MicroRNAs blood
- Abstract
The combination of liquid biomarkers from a single blood tube can provide more comprehensive information on tumor development and progression in cancer patients compared to single analysis. Here, we evaluated whether a combined analysis of circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), and circulating cell-free microRNA (miRNA) in total plasma and extracellular vesicles (EV) from the same blood sample is feasible and how the results are influenced by the choice of different blood tubes. Peripheral blood from 20 stage IV melanoma patients and five healthy donors (HD) was collected in EDTA, Streck, and Transfix tubes. Peripheral blood mononuclear cell fraction was used for CTC analysis, whereas plasma and EV fractions were used for ctDNA mutation and miRNA analysis. Mutations in cell-free circulating DNA were detected in 67% of patients, with no significant difference between the tubes. CTC was detected in only EDTA blood and only in 15% of patients. miRNA NGS (next-generation sequencing) results were highly influenced by the collection tubes and could only be performed from EDTA and Streck tubes due to hemolysis in Transfix tubes. No overlap of significantly differentially expressed miRNA (patients versus HD) could be found between the tubes in total plasma, whereas eight miRNA were commonly differentially regulated in the EV fraction. In summary, high-quality CTCs, ctDNA, and miRNA data from a single blood tube can be obtained. However, the choice of blood collection tubes is a critical pre-analytical variable., (© 2020 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.)
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- 2020
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12. D-dimers in malignant melanoma: Association with prognosis and dynamic variation in disease progress.
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Desch A, Gebhardt C, Utikal J, and Schneider SW
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- Adult, Aged, Aged, 80 and over, Biomarkers, Biomarkers, Tumor blood, C-Reactive Protein analysis, Disease-Free Survival, Female, Humans, Kaplan-Meier Estimate, L-Lactate Dehydrogenase blood, Male, Melanoma complications, Melanoma mortality, Melanoma pathology, Middle Aged, Neoplasm Invasiveness, Neovascularization, Pathologic blood, Neovascularization, Pathologic etiology, Prognosis, Proportional Hazards Models, Retrospective Studies, S100 Calcium Binding Protein beta Subunit blood, Skin Neoplasms complications, Skin Neoplasms mortality, Skin Neoplasms pathology, Thrombophilia blood, Thrombophilia etiology, Young Adult, Fibrin Fibrinogen Degradation Products analysis, Melanoma blood, Skin Neoplasms blood
- Abstract
Malignant cells elicit a chronic hemostatic activation in disease progress. This procoagulant activity does not only bear a risk for thromboembolism but also facilitates tumor growth and dissemination. An elevated plasma D-dimer level indicates an activated coagulation and fibrinolysis. In this study, the association of D-dimer levels with clinicopathological parameters and patients outcome in melanoma was investigated analyzing in total 533 melanoma patients retrospectively. Using the cut-off point of 0.6 mg/L D-dimer 145 of the total 533 patients (27.2%) were identified with elevated plasma D-dimer levels. This increased D-dimer level positively correlated with tumor thickness (p = 0.0003), lymph node invasion (p = 0.0004) and metastatic state (p <0.0001). To assess the association of D-dimer levels with progression-free survival (PFS) and overall survival (OS), long-rank test and the Cox proportional hazard model was performed. Univariate analyses revealed that elevated D-dimer levels were significantly associated with decreased PFS (HR:2.89, 95% CI (2.07-7.56), p < 0.0001) and OS (HR:2.22, 95% CI (1.06-4.57), p = 0.035). Moreover, multivariate analyses identified elevated D-dimer levels being associated with poor disease outcome (PFS:HR:2.47, 95% CI (1.23-4.98), p = 0.012; OS:HR:2.01, 95% CI (0.09-4.45), p = 0.087). Additionally, D-dimer levels were significantly increased in terminal stage patients when comparing plasma levels 0-8 versus 24-48 weeks before death (p = 0.0003). In summary, this study presents multiple evidence that elevated D-dimer levels in melanoma patients associate with poor prognosis and therefore plasma levels of D-dimers could reveal a more aggressive phenotype of melanoma and may guide the management of anti-melanoma treatment including the concept of an anti-coagulatory therapy in tumor patients., (© 2016 UICC.)
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- 2017
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13. von Willebrand factor fibers promote cancer-associated platelet aggregation in malignant melanoma of mice and humans.
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Bauer AT, Suckau J, Frank K, Desch A, Goertz L, Wagner AH, Hecker M, Goerge T, Umansky L, Beckhove P, Utikal J, Gorzelanny C, Diaz-Valdes N, Umansky V, and Schneider SW
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- ADAM Proteins blood, ADAM Proteins metabolism, ADAMTS13 Protein, Animals, Blood Coagulation, Blood Platelets, Disease Models, Animal, Disease Progression, Endothelial Cells metabolism, Enzyme Activation, Fibrinolytic Agents pharmacology, Heparin, Low-Molecular-Weight pharmacology, Humans, Melanoma blood, Melanoma pathology, Mice, Mice, Transgenic, Microvessels metabolism, Neovascularization, Pathologic metabolism, Protein Binding, Proto-Oncogene Proteins c-ret metabolism, Tinzaparin, Vascular Endothelial Growth Factor A antagonists & inhibitors, Vascular Endothelial Growth Factor A metabolism, Melanoma metabolism, Platelet Aggregation, von Willebrand Factor metabolism
- Abstract
Tumor-mediated procoagulatory activity leads to venous thromboembolism and supports metastasis in cancer patients. A prerequisite for metastasis formation is the interaction of cancer cells with endothelial cells (ECs) followed by their extravasation. Although it is known that activation of ECs and the release of the procoagulatory protein von Willebrand factor (VWF) is essential for malignancy, the underlying mechanisms remain poorly understood. We hypothesized that VWF fibers in tumor vessels promote tumor-associated thromboembolism and metastasis. Using in vitro settings, mouse models, and human tumor samples, we showed that melanoma cells activate ECs followed by the luminal release of VWF fibers and platelet aggregation in tumor microvessels. Analysis of human blood samples and tumor tissue revealed that a promoted VWF release combined with a local inhibition of proteolytic activity and protein expression of ADAMTS13 (a disintegrin-like and metalloproteinase with thrombospondin type I repeats 13) accounts for this procoagulatory milieu. Blocking endothelial cell activation by the low-molecular-weight heparin tinzaparin was accompanied by a lack of VWF networks and inhibited tumor progression in a transgenic mouse model. Our findings implicate a mechanism wherein tumor-derived vascular endothelial growth factor-A (VEGF-A) promotes tumor progression and angiogenesis. Thus, targeting EC activation envisions new therapeutic strategies attenuating tumor-related angiogenesis and coagulation., (© 2015 by The American Society of Hematology.)
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- 2015
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14. Melanoma-derived IL-1 converts vascular endothelium to a proinflammatory and procoagulatory phenotype via NFκB activation.
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Strozyk EA, Desch A, Poeppelmann B, Magnolo N, Wegener J, Huck V, and Schneider SW
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- Calcium Signaling, Capillary Permeability, Cell Line, Tumor, Cytokines metabolism, Disease Progression, Endothelium, Vascular metabolism, Endothelium, Vascular pathology, Humans, Inflammation metabolism, Intercellular Adhesion Molecule-1 metabolism, Interleukin-6 metabolism, Interleukin-8 metabolism, Melanoma blood supply, Melanoma pathology, Models, Biological, Phenotype, Thromboplastin metabolism, Up-Regulation, Vascular Cell Adhesion Molecule-1 metabolism, von Willebrand Factor metabolism, Interleukin-1 metabolism, Melanoma metabolism, NF-kappa B metabolism
- Abstract
Spreading of melanoma is associated with efficient extravasation of circulating tumor cells from the vascular system into distant target organs. This process is accompanied and supported by proinflammatory and procoagulatory conditions. In this study, we analysed the ability of human melanoma cell lines to activate endothelial cells (ECs) in vitro. Some melanoma cells, that is, MV3, were shown to trigger an prompt calcium-flux-dependent, procoagulatory endothelial response that was accompanied by luminal release of ultra-large von Willebrand factor (ULVWF) fibres that were immobilized to the endothelial surface layer. In contrast to MV3-derived supernatant, prolonged treatment of ECs with WM9-derived supernatant mediated a pronounced activation of nuclear factor kappa B (NFκB). NFκB activation in ECs was dependent on both IL-1α and IL-1β secreted from melanoma cells. Melanoma-derived IL-1 mediated an upregulation of proinflammatory cytokines IL-6 and IL-8, the intercellular adhesion molecule-1 (ICAM-1), the vascular cell adhesion molecule-1 (VCAM-1) and the procoagulatory tissue factor (TF) in ECs. Our data show that melanoma cells activate ECs either directly and within seconds or by an IL-1-mediated NFκB activation. Both pathways of EC activation convert the regular repressive function of ECs on inflammation and coagulation to a proinflammatory and procoagulatory surface that supports tumor progression., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
- Published
- 2014
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15. Desmoglein 2 depletion leads to increased migration and upregulation of the chemoattractant secretoneurin in melanoma cells.
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Peitsch WK, Doerflinger Y, Fischer-Colbrie R, Huck V, Bauer AT, Utikal J, Goerdt S, and Schneider SW
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- Bromodeoxyuridine, Cell Line, Tumor, Cell Movement genetics, Desmoglein 2 deficiency, Electric Impedance, Gene Expression Profiling, Humans, Immunoblotting, Immunohistochemistry, Microscopy, Fluorescence, RNA Interference, Radioimmunoassay, Real-Time Polymerase Chain Reaction, Reverse Transcriptase Polymerase Chain Reaction, Secretogranin II metabolism, Cell Movement physiology, Desmoglein 2 metabolism, Gene Expression Regulation physiology, Melanoma physiopathology
- Abstract
During development and progression of malignant melanoma, an important role has been attributed to alterations of cell-cell adhesions, in particular, to a "cadherin switch" from E- to N-cadherin. We have previously shown that a subtype of melanoma cells express the desmosomal cadherin desmoglein 2 as non-junction-bound cell surface protein in addition to classical cadherins. To study the role of desmoglein 2 in melanoma cells, melanoma lines containing high endogenous amounts of desmoglein 2 were depleted of the protein by RNA interference. Transwell migration and scratch wounding assays showed markedly increased migration upon desmoglein 2 suppression whereas proliferation and viability remained unaltered. In gene expression profiles, desmoglein 2 depletion was associated with overexpression of migration-related genes. Strongest overexpression was found for secretogranin II which has not been reported in melanoma cells before. The bioactive peptide derived from secretogranin II, secretoneurin, is known to exert chemoattractive functions and was demonstrated here to stimulate melanoma cell migration. In summary, we show that desmoglein 2 expression attenuates migration of melanoma cells. The mechanism of desmoglein 2 impaired cell migration is mediated by downregulation of secretogranin II. Loss of desmoglein 2 increases expression of secretogranin II, followed by an enhanced migratory activity of melanoma cells. Our data add a new pathway of regulating melanoma cell migration related to a desmoglein 2-secretogranin II axis.
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- 2014
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16. Highly invasive melanoma cells activate the vascular endothelium via an MMP-2/integrin αvβ5-induced secretion of VEGF-A.
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Desch A, Strozyk EA, Bauer AT, Huck V, Niemeyer V, Wieland T, and Schneider SW
- Subjects
- Adult, Animals, Cell Line, Tumor, Cell Membrane metabolism, Enzyme Activation, Gene Expression Regulation, Neoplastic, Gene Knockdown Techniques, Humans, Male, Matrix Metalloproteinase 14 metabolism, Melanoma blood supply, Melanoma genetics, Mice, Models, Biological, Neoplasm Invasiveness, Neovascularization, Pathologic genetics, Neovascularization, Pathologic pathology, Phosphatidylinositol 3-Kinases metabolism, RNA, Messenger genetics, RNA, Messenger metabolism, Signal Transduction, Skin Neoplasms blood supply, Skin Neoplasms enzymology, Skin Neoplasms genetics, Skin Neoplasms pathology, Vascular Endothelial Growth Factor A genetics, Vascular Endothelial Growth Factor Receptor-2 metabolism, von Willebrand Factor metabolism, Endothelium, Vascular enzymology, Endothelium, Vascular pathology, Matrix Metalloproteinase 2 metabolism, Melanoma enzymology, Melanoma pathology, Receptors, Vitronectin metabolism, Vascular Endothelial Growth Factor A metabolism
- Abstract
Tumor cell extravasation is a critical step in the metastatic cascade and requires interaction between the tumor cell and the endothelium. Although cancer progression depends on a complex network of mechanisms, including inflammation and coagulation, the involvement of tumor-induced endothelium activation and the subsequent release of procoagulatory factors in this process are not well understood. Using tissue sections from patients with malignant melanoma, immunofluorescence studies for the presence of von Willebrand factor (VWF) clearly demonstrated endothelium activation and the formation of ultra-large VWF fibers in these patients. In vitro analyses revealed that supernatants from highly invasive melanoma cells induced an acute endothelium activation measured by VWF, P-selectin, and angiopoietin-2 release. Proteome profiling identified vascular endothelial growth factor A (VEGF-A) as the main mediator of endothelium activation. Inhibition and knock-down of VEGF-A in melanoma cells led to a rigorous decrease in VWF exocytosis. Selective small-interfering RNA to matrix metalloproteinase-2 (MMP-2) inhibited endothelium activation, and this effect correlated with reduced VEGF-A content in the supernatants of melanoma cells. Further experiments showed that active MMP-2 regulates VEGF-A in melanoma cells on a transcriptional level via an integrin αvβ5/phosphoinositide-3-kinase-dependent pathway. In conclusion, these results indicate an important role of VEGF-A in acute endothelium activation and provide clear evidence that MMP-2 plays a pivotal role in the autocrine regulation of VEGF-A expression in melanoma cells., (Copyright © 2012 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)
- Published
- 2012
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17. Proteinase-activated receptors 1 and 2 regulate invasive behavior of human melanoma cells via activation of protein kinase D1.
- Author
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Kempkes C, Rattenholl A, Buddenkotte J, Strozyk E, Eberle J, Hausser A, Cevikbas F, Schneider SW, and Steinhoff M
- Subjects
- Cell Line, Tumor, Cell Shape, Enzyme Activation, Humans, Integrin alphaVbeta3 analysis, Interleukin-8 metabolism, Phosphorylation, Melanoma pathology, Receptor, PAR-1 physiology, Receptor, PAR-2 physiology, Skin Neoplasms pathology, TRPP Cation Channels physiology
- Abstract
Recent studies have indicated an important role of proteinases and proteinase-activated receptors (PARs) in tumorigenesis. Although a role for PARs has been described in various skin tumors including melanoma, the underlying cellular mechanisms have not been understood. Recent studies have suggested PAR(1) as a regulator of melanoma cell growth and metastasis by affecting angiogenic and invasive factors. Moreover, changes in the expression patterns of PAR(1) and PAR(2) correlate with skin cancer progression, and PAR(1) is overexpressed in melanoma. Therefore, we sought to elucidate the putative role of PAR(1)- and PAR(2)-mediated signal transduction pathways during melanoma progression. Activation of both PAR(1) and PAR(2) led to rapid phosphorylation of protein kinase D1 (PKD1) in cultured WM9 melanoma cells. PKD1 is known to be involved in cell migration, integrin regulation, and intracellular vesicle transport. Downregulation of PKD1 by siRNA resulted in diminished proliferation, decreased αvβ3 integrin regulation, and secretion of pro-angiogenic chemokine IL-8 in WM9 cells. In conclusion, our results show that PAR(1) and PAR(2) are involved in WM9 cell proliferation and secretion of IL-8 by activation of PKD1. Inactivation of the PKD1 pathway may be beneficial for the inhibition of PAR-induced melanoma proliferation and for maintenance of the inflammatory tumor environment.
- Published
- 2012
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18. Engagement of αIIbβ3 (GPIIb/IIIa) with ανβ3 integrin mediates interaction of melanoma cells with platelets: a connection to hematogenous metastasis.
- Author
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Lonsdorf AS, Krämer BF, Fahrleitner M, Schönberger T, Gnerlich S, Ring S, Gehring S, Schneider SW, Kruhlak MJ, Meuth SG, Nieswandt B, Gawaz M, Enk AH, and Langer HF
- Subjects
- Animals, Antibodies, Neutralizing pharmacology, Blood Platelets pathology, Bone Marrow Neoplasms genetics, Bone Marrow Neoplasms pathology, CHO Cells, Cell Adhesion drug effects, Cell Adhesion genetics, Cricetinae, Cricetulus, Female, Humans, Melanoma genetics, Melanoma pathology, Mice, Neoplasm Metastasis, Platelet Glycoprotein GPIIb-IIIa Complex antagonists & inhibitors, Platelet Glycoprotein GPIIb-IIIa Complex genetics, Blood Platelets metabolism, Bone Marrow Neoplasms metabolism, Bone Marrow Neoplasms secondary, Melanoma metabolism, Platelet Glycoprotein GPIIb-IIIa Complex metabolism
- Abstract
A mutual relationship exists between metastasizing tumor cells and components of the coagulation cascade. The exact mechanisms as to how platelets influence blood-borne metastasis, however, remain poorly understood. Here, we used murine B16 melanoma cells to observe functional aspects of how platelets contribute to the process of hematogenous metastasis. We found that platelets interfere with a distinct step of the metastasis cascade, as they promote adhesion of melanoma cells to the endothelium in vitro under shear conditions. Constitutively active platelet receptor GPIIb/IIIa (integrin αIIbβ3) expressed on Chinese hamster ovary cells promoted melanoma cell adhesion in the presence of fibrinogen, whereas blocking antibodies to aνβ3 integrin on melanoma cells or to GPIIb/IIIa significantly reduced melanoma cell adhesion to platelets. Furthermore, using intravital microscopy, we observed functional platelet-melanoma cell interactions, as platelet depletion resulted in significantly reduced melanoma cell adhesion to the injured vascular wall in vivo. Using a mouse model of hematogenous metastasis to the lung, we observed decreased metastasis of B16 melanoma cells to the lung by treatment with a mAb blocking the aν subunit of aνβ3 integrin. This effect was significantly reduced when platelets were depleted in vivo. Thus, the engagement of GPIIb/IIIa with aνβ3 integrin interaction mediates tumor cell-platelet interactions and highlights how this interaction is involved in hematogenous tumor metastasis.
- Published
- 2012
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19. The mechanism of melanoma-associated thrombin activity and von Willebrand factor release from endothelial cells.
- Author
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Kerk N, Strozyk EA, Pöppelmann B, and Schneider SW
- Subjects
- Anticoagulants pharmacology, Cell Line, Tumor, Endothelial Cells drug effects, Enoxaparin pharmacology, Flow Cytometry, Heparin pharmacology, Heparin, Low-Molecular-Weight pharmacology, Humans, Melanoma secondary, RNA, Small Interfering, Skin Neoplasms pathology, Thromboplastin genetics, Thromboplastin metabolism, Tinzaparin, Endothelial Cells metabolism, Melanoma metabolism, Prothrombin metabolism, Skin Neoplasms metabolism, Thrombin metabolism, von Willebrand Factor metabolism
- Abstract
Activation of the coagulation system in malignancy enables tumor spreading and is thus associated with poor prognosis for the patient. In this study, we analyzed the in vitro mechanisms by which two human metastatic melanoma cell lines, MV3 and WM9, transform the vascular endothelium into a prothrombotic activated state. We show that both melanoma cell lines activate prothrombin due to tissue factor (TF) expression by showing that thrombin generation was blocked with a TF-neutralizing antibody and TF-siRNA. In addition, using the cysteine protease inhibitor E-64, we excluded the formerly described cancer procoagulant (CP) as a major factor contributing to thrombin generation. Furthermore, we describe a direct thrombin-independent response of endothelial cells (ECs) to MV3-derived supernatant as measured by rapid release of VWF. We also show that two clinically approved LMWHs, tinzaparin and enoxaparin, are effective inhibitors of thrombin generation and thrombin activity in plasma. Furthermore, our data indicate a protective effect of heparins on EC activation as shown by reduced VWF release in response to MV3 supernatant. These promising effects of heparins on the melanoma-induced thrombotic conditions justify further clinical investigations in the field of oncology.
- Published
- 2010
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20. Inhibition of hyaluronan export attenuates cell migration and metastasis of human melanoma.
- Author
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Monz K, Maas-Kück K, Schumacher U, Schulz T, Hallmann R, Schnäker EM, Schneider SW, and Prehm P
- Subjects
- Cell Adhesion, Cell Line, Tumor, Cell Proliferation, Humans, Neoplasm Invasiveness, Neoplasm Metastasis, Purinones pharmacology, Cell Movement physiology, Hyaluronic Acid metabolism, Melanoma pathology
- Abstract
When secreted from malignant cells, hyaluronan facilitates tumor invasion and metastasis, as inhibition of its export by zaprinast inhibited metastasis formation in mice. However, the precise steps of the metastatic cascade, which were influenced by zaprinast, have not been identified as yet. Here we analyzed the cell biological effects of the inhibitor on three human melanoma cell lines that differed in their hyaluronan production and their metastatic capability when xenografted into SCID mice. We measured the influence of zaprinast on cellular hyaluronan export, surface coat formation, proliferation, random migration, colony formation in soft agar, adhesion, and transepithelial resistance. Concentrations of zaprinast not affecting cell proliferation, adhesion and transepithelial resistance, nevertheless reduced hyaluronan export by 50%, surface coat formation, random migration, and colony formation in soft agar. These results indicate that hyaluronan enhances metastasis formation primarily in those steps of the metastatic cascade, which involves tumor cell migration.
- Published
- 2008
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21. Specific interaction between chitosan and matrix metalloprotease 2 decreases the invasive activity of human melanoma cells.
- Author
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Gorzelanny C, Pöppelmann B, Strozyk E, Moerschbacher BM, and Schneider SW
- Subjects
- Animals, Cell Line, Tumor, Cell Movement, Cell Proliferation, Chromatography, Affinity methods, Dogs, Gelatin chemistry, Humans, Microscopy, Atomic Force, Models, Biological, Neoplasm Invasiveness, Skin Neoplasms pathology, Chitosan chemistry, Matrix Metalloproteinase 2 metabolism, Melanoma metabolism
- Abstract
The crucial event in metastasis is tumor invasion which in the case of melanoma cells is dependent on matrix metalloprotease 2 (MMP2). Chitosan (MW ca. 5 x 10(5) g mol(-1), degree of acetylation ca. 30%) attenuated the invasive activity of melanoma cells in a cell-based invasion assay and reduced MMP2 activity in the supernatant of melanoma cells. While the expression level of MMP2 was not affected, the amount of MMP2 in the cell supernatant was reduced, indicating a posttranscriptional effect of chitosan on MMP2. Atomic force microscopy revealed a direct molecular interaction between MMP2 and chitosan forming a complex with a diameter of 349.0 +/- 69.06 nm and a height of 26.5 +/- 11.50 nm. Affinity chromatography revealed a high binding-specificity of MMP2 to chitosan, and a colorimetric MMP2 activity assay suggests a noncompetitive inhibition of MMP2 by chitosan. The possible use of chitosan as a new type of MMP2 inhibitor is discussed.
- Published
- 2007
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22. Tumor-derived matrix metalloproteinase-1 targets endothelial proteinase-activated receptor 1 promoting endothelial cell activation.
- Author
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Goerge T, Barg A, Schnaeker EM, Poppelmann B, Shpacovitch V, Rattenholl A, Maaser C, Luger TA, Steinhoff M, and Schneider SW
- Subjects
- Animals, Caco-2 Cells, Calcium metabolism, Cattle, Colonic Neoplasms blood supply, Colonic Neoplasms enzymology, Endothelial Cells cytology, HT29 Cells, Humans, Matrix Metalloproteinase Inhibitors, Melanoma blood supply, Melanoma enzymology, Receptor, PAR-1 antagonists & inhibitors, Colonic Neoplasms metabolism, Endothelial Cells metabolism, Matrix Metalloproteinase 1 metabolism, Melanoma metabolism, Receptor, PAR-1 metabolism
- Abstract
In the vascular system, circulating tumor cells interact with endothelial cells. Tumor-endothelial cross-talk transforms the intravascular milieu to a prothrombotic, proinflammatory, and cell-adhesive state called endothelial cell activation (ECA). In the present study, we analyze the potential of metastatic tumor-derived soluble factors to transform the vascular endothelium into a prothrombotic and proinflammatory activated state. Supernatant from cultured melanoma and colon cancer cells (A375, WM9, A7, and HT-29) induced an acute activation of macrovascular and microvascular endothelial cells (human umbilical vein endothelial cells and human dermal microvascular endothelial cells) as shown by intracellular calcium flux and secretion of von Willebrand factor and interleukin-8, all markers of acute ECA. This process was inhibited using specific proteinase-activated receptor 1 (PAR1) inhibitors (RWJ-58259 and SCH-79797), indicating a mediating role for endothelial thrombin receptors. Immunofluorescence, Western blot analysis, and collagenase activity assay of tumor cells and culture supernatant revealed the presence of matrix metalloproteinase-1 (MMP-1), a recently described activator of PAR1. Inhibition of MMP-1 in supernatant from cultured tumor cells significantly attenuated ECA. Additional studies using isolated human MMP-1 (5 nmol/L) proved the presence of a functional MMP-1/PAR1 axis in tumor-endothelial communication. These findings show a new pathway of tumor-endothelial cross-talk via an intravascular MMP1/PAR1 axis in microvascular and macrovascular endothelium. Inhibition of this cross-talk may be a powerful means to prevent tumor-induced ECA and thus thrombotic and inflammatory cell adhesion.
- Published
- 2006
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23. The electrical resistance breakdown assay determines the role of proteinases in tumor cell invasion.
- Author
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Ludwig T, Ossig R, Graessel S, Wilhelmi M, Oberleithner H, and Schneider SW
- Subjects
- Animals, Basement Membrane enzymology, Cell-Free System, Coculture Techniques, Collagenases metabolism, Electric Impedance, Exocytosis physiology, Humans, Hydroxamic Acids, Indoles pharmacology, Matrix Metalloproteinase Inhibitors, Neoplasm Invasiveness, Protease Inhibitors pharmacology, Tumor Cells, Cultured enzymology, Tumor Cells, Cultured pathology, Kidney cytology, Matrix Metalloproteinases metabolism, Melanoma
- Abstract
The electrical resistance breakdown of the Madin-Darby canine kidney (MDCK) cell monolayer provides a continuous assay system for cancer invasion that detects functional changes before morphological alterations. In this study, we address the question of whether physical contact between tumor cell and epithelial monolayer is a prerequisite for tumor cell invasion. When human melanoma cells were seeded directly (i.e., physical contact) on top of an electrically tight epithelial cell layer (5,800 +/- 106 Omega x cm2), electrical monolayer leakage led to an 18 +/- 3% reduction of transepithelial electrical resistance within 24 h. However, when melanoma cells were seeded close to the basolateral surface of the epithelial cell monolayer but separated by a filter membrane (i.e., no physical contact), electrical leakage occurred even more quickly (42 +/- 3% reduction in 24 h). Atomic force microscopy detected discrete structural changes between cells. Electrical leakage was effectively blocked by alpha2-macroglobulin or ilomastat, inhibitors of matrix metalloproteinases. We conclude that exocytosis of soluble proteases causes electrical breakdown of the MDCK monolayer, independently of physical contact between tumor cells and the monolayer.
- Published
- 2002
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24. High Serum Levels of CCL20 Are Associated with Recurrence and Unfavorable Overall Survival in Advanced Melanoma Patients Receiving Immunotherapy.
- Author
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Kött, Julian, Hoehne, Inka Lilott, Heidrich, Isabel, Zimmermann, Noah, Reese, Kim-Lea, Zell, Tim, Geidel, Glenn, Rünger, Alessandra, Schneider, Stefan W., Pantel, Klaus, Smit, Daniel J., and Gebhardt, Christoffer
- Subjects
MELANOMA prognosis ,CHEMOKINES ,MELANOMA ,CANCER relapse ,SURVIVAL rate ,RESEARCH funding ,IMMUNOTHERAPY ,DESCRIPTIVE statistics ,TUMOR markers ,NIVOLUMAB ,PROGRESSION-free survival ,CONFIDENCE intervals ,IPILIMUMAB ,PROPORTIONAL hazards models - Abstract
Simple Summary: In this prospective cohort study of metastatic melanoma patients receiving immune checkpoint inhibitors, we identified a serum chemokine CCL20 increase at baseline with a significantly impaired progression-free and overall survival and as an independent negative prognostic factor for PFS and OS in univariate as well as in multivariate analysis. CCL20 may represent a novel blood biomarker for the prediction of prognosis in advanced melanoma under immunotherapy with a special emphasis on progression. Background: Immune checkpoint inhibition has revolutionized melanoma therapy, but many patients show primary or secondary resistance. Biomarkers are, therefore, urgently required to predict response prior to the initiation of therapy and to monitor disease progression. Methods: In this prospective study, we analyzed the serum C-C motif chemokine ligand 20 (CCL20) concentration using an enzyme-linked immunosorbent assay. Blood was obtained at baseline before the initiation of immunotherapy with anti-PD-1 monotherapy or Nivolumab and Ipilimumab in advanced melanoma patients (stages III and IV) enrolled at the University Medical Center Hamburg-Eppendorf. The CCL20 levels were correlated with clinico-pathological parameters and disease-related outcomes. Results: An increased C-C motif chemokine ligand 20 (CCL20) concentration (≥0.34 pg/mL) at baseline was associated with a significantly impaired progression-free survival (PFS) in the high-CCL20 group (3 months (95% CI: 2–6 months) vs. 11 months (95% CI: 6–26 months)) (p = 0.0033) and could be identified as an independent negative prognostic factor for PFS in univariate (Hazard Ratio (HR): 1.98, 95% CI 1.25–3.12, p = 0.004) and multivariate (HR: 1.99, 95% CI 1.21–3.29, p = 0.007) Cox regression analysis, which was associated with a higher risk than S100 (HR: 1.74). Moreover, high CCL20 levels were associated with impaired overall survival (median OS not reached for low-CCL20 group, p = 0.042) with an HR of 1.85 (95% CI 1.02–3.37, p = 0.043) in univariate analysis similar to the established prognostic marker S100 (HR: 1.99, 95% CI: 1.02–3.88, p = 0.043). Conclusions: CCL20 may represent a novel blood-based biomarker for the prediction of resistance to immunotherapy that can be used in combination with established strong clinical predictors (e.g., ECOG performance score) and laboratory markers (e.g., S100) in advanced melanoma patients. Future prospective randomized trials are needed to establish CCL20 as a liquid biopsy-based biomarker in advanced melanoma. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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25. Activated Eosinophils Predict Longer Progression-Free Survival under Immune Checkpoint Inhibition in Melanoma.
- Author
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Ammann, Nadine L., Schwietzer, Yasmin F., Mess, Christian, Stadler, Julia-Christina, Geidel, Glenn, Kött, Julian, Pantel, Klaus, Schneider, Stefan W., Utikal, Jochen, Bauer, Alexander T., and Gebhardt, Christoffer
- Subjects
EOSINOPHILS ,DISEASE progression ,IMMUNE checkpoint inhibitors ,MELANOMA ,FLUOROIMMUNOASSAY ,METASTASIS ,PROGRESSION-free survival ,T cells ,CELL lines - Abstract
Simple Summary: Immune checkpoint inhibitors, which stimulate the patient's own T-cells to attack tumor cells, have revolutionized the treatment of metastatic melanoma. However, not all melanoma patients respond to therapy possibly due to a lack of T-cells present in or entering tumor tissue. It is presumed that eosinophils could aid T-cell-mediated immune response against tumor cells. In order to describe the local association of eosinophils and T-cells within the tumor microenvironment we investigated specific markers for cell type and activation status using immunofluorescence. Additionally, blood measurements were performed to determine the effects of eosinophil count and their activation status on the efficacy of immune checkpoint inhibition. There was a strong correlation between activated eosinophils and T-cells in melanoma. Furthermore, patients with high blood levels of activated eosinophils showed a delayed tumor progression. In the future, eosinophils may serve as prognostic biomarkers as well as novel therapeutic targets in melanoma. Immune checkpoint inhibition (ICI) has yielded remarkable results in prolonging survival of metastatic melanoma patients but only a subset of individuals treated respond to therapy. Success of ICI treatment appears to depend on the number of tumor-infiltrating effector T-cells, which are known to be influenced by activated eosinophils. To verify the co-occurrence of activated eosinophils and T-cells in melanoma, immunofluorescence was performed in 285 primary or metastatic tumor tissue specimens from 118 patients. Moreover, eosinophil counts and activity markers such as eosinophil cationic protein (ECP) and eosinophil peroxidase (EPX) were measured in the serum before therapy start and before the 4th infusion of ICI in 45 metastatic unresected melanoma patients. We observed a positive correlation between increased tumor-infiltrating eosinophils and T-cells associated with delayed melanoma progression. High baseline levels of eosinophil count, serum ECP and EPX were linked to prolonged progression-free survival in metastatic melanoma. Our data provide first indications that activated eosinophils are related to the T-cell-inflamed tumor microenvironment and could be considered as potential future prognostic biomarkers in melanoma. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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26. Successful treatment of PD‐1 inhibitor‐induced psoriasis with infliximab.
- Author
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Hansen, Inga, Heidrich, Isabel, Abeck, Finn, Kött, Julian, Booken, Nina, Gebhardt, Christoffer, and Schneider, Stefan W.
- Subjects
TREATMENT effectiveness ,PROGRAMMED cell death 1 receptors ,PSORIASIS ,INFLIXIMAB ,DRUG side effects ,MELANOMA - Abstract
When deciding on systemic therapy for irAE psoriasis, it should be considered that TNF-alpha inhibitors might improve the response to treatment with ICI and thus the prognosis of the tumour disease. Immune checkpoint inhibitors (ICI) have become firmly established in the treatment of malignant melanoma (MM) and have significantly improved prognosis in advanced tumour stages.[[1]] Recently, the anti-programmed death 1 (PD-1) agent Pembrolizumab showed a significant reduction in the risk of disease recurrence for stage IIB or IIC MM.[2] As ICI interferes with immunoregulatory pathways by blocking checkpoints, non-specific activation of the immune system can result in the development of immune-related adverse events (irAE).[3] In patients receiving monotherapy with a PD-1 inhibitor, grade 3 or 4 irAEs occurred in 23% with nivolumab and in 16% with pembrolizumab.[[1]] The spectrum of cutaneous irAE is diverse and most commonly present as maculopapular exanthema with pruritus.[[3]] Another possible manifestation is psoriasis.[5] Treatment with biologics has been established in the therapy of severe psoriasis, one option being tumour necrosis factor (TNF)-alpha inhibitors.[6] Inflammatory signals such as TNF are essential factors that determine the aggressiveness of melanoma cells.[7] There is evidence that concomitant therapy with a TNF-alpha inhibitor may have positive effects on treatment response and thus tumour prognosis.[8] We report on a 67-year-old man with stage IIB MM. In the further course, the psoriasis was progressive; therefore, therapy with Nivolumab was terminated after six times at the patient's request. [Extracted from the article]
- Published
- 2023
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27. Neutrophils activated by membrane attack complexes increase the permeability of melanoma blood vessels.
- Author
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Xiaobo Liu, Yuanyuan Wang, Bauer, Alexander T., Kirschfink, Michael, Peipei Ding, Gebhardt, Christoffer, Borsig, Lubor, Tüting, Thomas, Renné, Thomas, Häffner, Karsten, Weiguo Hu, Schneider, Stefan W., and Gorzelanny, Christian
- Subjects
BLOOD vessels ,NEUTROPHILS ,VASCULAR endothelium ,MELANOMA ,COMPLEMENT activation - Abstract
The microenvironment of malignant melanomas defines the properties of tumor blood vessels and regulates infiltration and vascular dissemination of immune and cancer cells, respectively. Previous research in other cancer entities suggested the complement system as an essential part of the tumor microenvironment. Here, we confirm activation of the complement system in samples of melanoma patients and murine melanomas. We identified the tumor endothelium as the starting point of the complement cascade. Generation of complement-derived C5a promoted the recruitment of neutrophils. Upon contact with the vascular endothelium, neutrophils were further activated by complement membrane attack complexes (MACs). MAC-activated neutrophils release neutrophil extracellular traps (NETs). Close to the blood vessel wall, NETs opened the endothelial barrier as indicated by an enhanced vascular leakage. This facilitated the entrance of melanoma cells into the circulation and their systemic spread. Depletion of neutrophils or lack of MAC formation in complement component 6 (C6)-deficient animals protected the vascular endothelium and prevented vascular intravasation of melanoma cells. Our data suggest that inhibition of MAC-mediated neutrophil activation is a potent strategy to abolish hematogenous dissemination in melanoma. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
28. CD74 and CD44 Expression on CTCs in Cancer Patients with Brain Metastasis.
- Author
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Loreth, Desiree, Schuette, Moritz, Zinke, Jenny, Mohme, Malte, Piffko, Andras, Schneegans, Svenja, Stadler, Julia, Janning, Melanie, Loges, Sonja, Joosse, Simon A., Lamszus, Katrin, Westphal, Manfred, Müller, Volkmar, Glatzel, Markus, Matschke, Jakob, Gebhardt, Christoffer, Schneider, Stefan W., Belczacka, Iwona, Volkmer, Beate, and Greinert, Rüdiger
- Subjects
BRAIN metastasis ,CANCER patients ,BREAST cancer ,BREAST ,NON-small-cell lung carcinoma ,BRAIN cancer - Abstract
Up to 40% of advance lung, melanoma and breast cancer patients suffer from brain metastases (BM) with increasing incidence. Here, we assessed whether circulating tumor cells (CTCs) in peripheral blood can serve as a disease surrogate, focusing on CD44 and CD74 expression as prognostic markers for BM. We show that a size-based microfluidic approach in combination with a semi-automated cell recognition system are well suited for CTC detection in BM patients and allow further characterization of tumor cells potentially derived from BM. CTCs were found in 50% (7/14) of breast cancer, 50% (9/18) of non-small cell lung cancer (NSCLC) and 36% (4/11) of melanoma patients. The next-generation sequencing (NGS) analysis of nine single CTCs from one breast cancer patient revealed three different CNV profile groups as well as a resistance causing ERS1 mutation. CD44 and CD74 were expressed on most CTCs and their expression was strongly correlated, whereas matched breast cancer BM tissues were much less frequently expressing CD44 and CD74 (negative in 46% and 54%, respectively). Thus, plasticity of CD44 and CD74 expression during trafficking of CTCs in the circulation might be the result of adaptation strategies. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
29. Intra-Patient Heterogeneity of Circulating Tumor Cells and Circulating Tumor DNA in Blood of Melanoma Patients.
- Author
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Gorges, Katharina, Wiltfang, Lisa, Gorges, Tobias M., Sartori, Alexander, Hildebrandt, Lina, Keller, Laura, Volkmer, Beate, Peine, Sven, Babayan, Anna, Moll, Ingrid, Schneider, Stefan W., Twarock, Sören, Mohr, Peter, Fischer, Jens W., and Pantel, Klaus
- Subjects
BIOMARKERS ,CANCER patient psychology ,DNA ,EXTRACELLULAR space ,GENETICS ,MELANOMA ,METASTASIS ,GENETIC mutation ,NUCLEIC acids ,RNA ,BLOOD - Abstract
Despite remarkable progress in melanoma therapy, the exceptional heterogeneity of the disease has prevented the development of reliable companion biomarkers for the prediction or monitoring of therapy responses. Here, we show that difficulties in detecting blood-based markers, like circulating tumor cells (CTC), might arise from the translation of the mutational heterogeneity of melanoma cells towards their surface marker expression. We provide a unique method, which enables the molecular characterization of clinically relevant CTC subsets, as well as circulating tumor DNA (ctDNA), from a single blood sample. The study demonstrates the benefit of a combined analysis of ctDNA and CTC counts in melanoma patients, revealing that CTC subsets and ctDNA provide synergistic real-time information on the mutational status, RNA and protein expression of melanoma cells in individual patients, in relation to clinical outcome. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
30. Nuclear heparanase-1 activity suppresses melanoma progression via its DNA-binding affinity
- Author
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Alexander Bauer, Dorde Komljenovic, Yi Yang, Marko Roblek, Lubor Borsig, Stefan W. Schneider, Tobias Bäuerle, Christian Gorzelanny, Natalia Halter, University of Zurich, and Schneider, Stefan W
- Subjects
Vascular Endothelial Growth Factor A ,Cancer Research ,610 Medicine & health ,Biology ,10052 Institute of Physiology ,Madin Darby Canine Kidney Cells ,chemistry.chemical_compound ,Mice ,Dogs ,1311 Genetics ,Cell Line, Tumor ,Genetics ,Extracellular ,medicine ,1312 Molecular Biology ,Animals ,Humans ,Heparanase ,1306 Cancer Research ,Molecular Biology ,Melanoma ,Glucuronidase ,Cell Nucleus ,Gene knockdown ,NF-kappa B ,DNA ,Neoplasms, Experimental ,medicine.disease ,Vascular endothelial growth factor ,chemistry ,Tumor progression ,Lymphatic Metastasis ,Immunology ,Cancer cell ,Cancer research ,Disease Progression ,570 Life sciences ,biology ,Intracellular - Abstract
Heparanase-1 (HPSE) plays a pivotal role in structural remodeling of the ECM and the glycocalyx, thus conferring protumorigenic, proangiogenic and prometastatic properties to many cancer entities. In addition to its extracellular function, recent studies suggest an intracellular activity of HPSE with a largely unknown significance during tumor progression. Therefore, we investigated the relevance of the dual functions of HPSE to malignant melanoma in vitro, as well as in different mouse melanoma models based on the intradermal or intravenous injection of melanoma cells. Consistent with its extracellular action, an HPSE deficiency led to a reduced shedding of the glycocalyx accompanied by a reduced availability of vascular endothelial growth factor, affecting tumor growth and vascularization. In contrast, we measured an elevated expression of the protumorigenic factors pentraxin-3, tissue factor, TNF-α and most prominently, MMP-9, upon HPSE knockdown. In vivo, an HPSE deficiency was related to increased lymph node metastasis. Since the inhibition of its extracellular function with heparin was unable to block the gene regulatory impact of HPSE, we proposed an intracellular mechanism. Immunostaining revealed a counter-staining of HPSE and NF-κB in the nucleus, suggesting a close relationship between both proteins. This finding was further supported by the discovery of a direct charge-driven molecular interaction between HPSE and DNA by using atomic force microscopy and a co-precipitation approach. Our findings are novel and point towards a dual function for HPSE in malignant melanoma with a protumorigenic extracellular activity and a tumor-suppressive nuclear action. The identification of molecular strategies to shuttle extracellular HPSE into the nuclei of cancer cells could provide new therapeutic options.
- Published
- 2014
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